tbuckley/cabot-search huggingface dataset:
Abstract 98: The role of HORMAD1 in transformation of keratinocytes following vemurafenib treatment
Authors: Jennifer Gantchev, Amelia Martinez Villarreal, Brandon Ramchatesingh, Ivan V. Litvinov
Journal: Cancer Research (2022)

Abstract BRAF inhibitor (BRAFi) therapies are highly effective treatments for metastatic melanoma. However, BRAFi monotherapies are associated with a significant risk of squamous cell carcinoma (SCC) development in melanoma patients. Consequently, BRAF inhibition results in an unanticipated activation of the MAPK pathway in surrounding cells that harbour wildtype BRAF. Fortunately, a combination approach with both a BRAFi and the selective MAPK inhibitor (MEKi), trametinib, attenuates BRAFi-induced risk of SCCs. Despite the fact that this combination therapy is widely used in clinical practice, the mechanisms associated with SCC induction and why this effect is attenuated with a MEK inhibitor remain poorly understood. HORMAD1, a meiosis specific gene, has been shown to have an impact on genomic instability and proliferation in the development of SCCs. Moreover, recent work in our lab has demonstrated that the MAPK pathway regulates HORMAD1 expression in SCC cell lines. Therefore, we sought to investigate a potential role of HORMAD1 in the risk and development of SCCs as a mechanism of BRAFi that is attenuated with the co-administration of the MEKi, trametinib. Using the BRAFi, vemurafenib, we inhibited the kinase activity of activated BRAF (V600E) and the MEKi, trametinib to evaluate the expression of HORMAD1 in melanoma and normal keratinocyte cell lines. To determine the effects of these two inhibitors, a cell proliferation assay was conducted followed by the evaluation of various components of cell cycle regulation and genomic instability. We found that HORMAD1 protein expression levels increased following treatment with the BRAFi, vemurafenib, in the normal keratinocyte cell line, HaCaT, but not in the melanoma cell line, A375. In contrast, HORMAD1 expression decreased following treatment with the MEKi, trametinib in both HaCaT and A375. Cell proliferation assays depict a vulnerability to both vemurafenib and trametinib in both normal and melanoma cell lines, however, HaCaT cells appear to be more susceptible to increased levels of genomic instability following treatment with vemurafenib when compared to A375. Our results suggest that HORMAD1 likely plays a key role in the development of SCCs by increasing genomic instability and proliferation in normal keratinocytes following BRAFi monotreatment. The increased risk of SCC formation is attenuated by dampening HORMAD1 levels with the co-administration of the MEKi, trametinib. Citation Format: Jennifer Gantchev, Amelia Martinez Villarreal, Brandon Ramchatesingh, Ivan V. Litvinov. The role of HORMAD1 in transformation of keratinocytes following vemurafenib treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 98.
Abstract 500: Neuropsychological symptoms in patients with head and neck cancer undergoing radiation therapy: A network analysis
Authors: Yufen Lin, Deborah W. Bruner, Sudeshna Paul, Andrew H. Miller, Nabil F. Saba, Kristin A. Higgins, Dong M. Shin, Wenhui Zhang, Christine Miaskowski, Canhua Xiao
Journal: Cancer Research (2022)

Abstract Objectives: Patients with head and neck cancer experience neuropsychological symptoms (NPS) (i.e., depression, fatigue, sleep disturbance, pain, and cognitive dysfunction) during radiation therapy (RT) that decrease their functional status and quality of life. The purposes of this study were to examine and visualize the relationships among NPS within networks over time and evaluate demographic and clinical characteristics associated with symptom networks. Methods: A total of 192 patients (mean age 59.5±10.1 years, 75% male, 81% White) completed symptom questionnaires four times, namely, before RT (T1), 1 month (T2), 3 months (T3), and 1 year (T4) after RT. Network analysis was used to explore relationships among the five common NPS. Centrality indices, including strength, closeness, and betweenness, were used to describe the degrees of symptom interconnection. The network comparison test was used to assess the differences between two symptom networks. Results: Depression (reported by 13%-24% of patients) was associated with the other four symptoms, and fatigue (reported by 54%-77% of patients) was associated with the other three symptoms across four times. Based on centrality indices, depression (rstrength=1.1-1.4, rcloseness=0.07-0.08, rbetweeness=4-12) was the most central symptom in all four symptom networks, followed by fatigue (rstrength=0.8-1.0, rcloseness=0.05-0.06, rbetweeness=0-2). Higher levels of stress and no alcohol use were associated with stronger symptom networks in network global strength (low stress: 1.49 vs. moderate to high stress: 1.92; p=0.02; no alcohol use: 2.38 vs. alcohol use: 1.75; p=0.01), but not in network structure or edge strength prior to RT. No significant differences were found in other time points. Conclusions: Network analysis provided a novel approach to gain insights into the relationships of co-occurring NPS and identify central symptoms and associated characteristics. Clinicians can use this information to develop personalized symptom management interventions that target central symptoms and interactions within a network. Citation Format: Yufen Lin, Deborah W. Bruner, Sudeshna Paul, Andrew H. Miller, Nabil F. Saba, Kristin A. Higgins, Dong M. Shin, Wenhui Zhang, Christine Miaskowski, Canhua Xiao. Neuropsychological symptoms in patients with head and neck cancer undergoing radiation therapy: A network analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 500.
Letter to the Editor: An ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection
Authors: Hua Bao, Zheng Wang, Xiaoji Ma, Wei Guo, Xiangyu Zhang, Wanxiangfu Tang, Xin Chen, Xinyu Wang, Yikuan Chen, Shaobo Mo, Naixin Liang, Qianli Ma, Shuyu Wu, Xiuxiu Xu, Shuang Chang, Yulin Wei, Xian Zhang, Hairong Bao, Rui Liu, Shanshan Yang, Ya Jiang, Xue Wu, Yaqi Li, Long Zhang, Fengwei Tan, Qi Xue, Fangqi Liu, Sanjun Cai, Shugeng Gao, Junjie Peng, Jian Zhou, Yang Shao
Journal: Molecular Cancer (2022)

Abstract Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients ( N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.
Abstract LB520: A pharmacodynamic platform using liquid biopsy to support dose selection for the ATR inhibitor ART0380 (IACS-030380)
Authors: Manish Patel, Kathleen N. Moore, Desiree Piscitello, Jayesh Majithiya, Marina Roy Luzarraga, Helen Millward, Sarah V. Holt, Melissa Johnson
Journal: Cancer Research (2022)

Abstract Inhibition of ataxia telangiectasia and Rad-3 related (ATR) kinase offers therapeutic promise for DNA damage response deficient tumors. In addition, ATR inhibitors may offer even broader clinical utility when combined with PARPi’s, chemo, immune or radiation therapy. Flat-fixed dosing of ATR inhibitors alone or in combination has provided clinical benefit but is associated with on target, dose limiting haematological toxicity. Strategies to refine dose selection of this class of medicine may further optimize clinical benefit. The aim of our ongoing investigation is to determine if the dose selection for clinical development of the novel ATR inhibitor ART0380 (IACS-030380) may be optimized based on the degree of PD engagement in both tumor and normal tissue from patients. To do this, we have utilized in vitro and in vivo cancer models to help us understand the dynamic and temporal response to several biomarkers of ATR inhibition and DNA damage. Once established in vitro, we selected key markers, such as γH2AX and pKAP1, to explore in vivo using doses predicted to be biologically effective in man and have shown that these are modulated following exposure to ART0380. To enable the serial assessment of PD engagement in both tumor and normal tissue, we have developed an assay in the phase 1 study of ART0380 (NCT04657068) to measure γH2AX levels in circulating tumor cells (CTC’s) and normal cells (PBMC’s). A significant advantage of this approach is that samples are taken from the same blood draw and at several timepoints following exposure to ART0380. So far, our studies have shown that in patients, who have experienced drug exposures predicted to be biologically effective, γH2AX levels in CTC’s increase by up to 20% respectively from baseline while γH2AX in PBMC’s remains unaffected. This observation may highlight that target engagement has taken place for ART0380 in the tumor without an effect in normal tissue, a phenomena perhaps explained by the pharmacokinetic profile of ART0380. The clinical study is ongoing and we continue to monitor individual patient responses, toxicity, and correlate with PD engagement in tumor and normal tissue circulating biopsies. In addition, we are now expanding our analysis into a multiplexed assay where we will measure pKAP1 as well as γH2AX to build a more detailed assessment of PD activity in patients. Updated data will be presented. Citation Format: Manish Patel, Kathleen N. Moore, Desiree Piscitello, Jayesh Majithiya, Marina Roy Luzarraga, Helen Millward, Sarah V. Holt, Melissa Johnson. A pharmacodynamic platform using liquid biopsy to support dose selection for the ATR inhibitor ART0380 (IACS-030380) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB520.
Abstract 171: ERK dynamics are essential for colon tissue patterning
Authors: Kelvin W. Pond, Jayati Chakrabarti, Curtis A. Thorne, Andrew L. Paek
Journal: Cancer Research (2022)

Abstract Maintaining the correct ratio of cellular niches in space and time allows tissues to perform their complex functions and create patterns. This maintenance of tissue patterning is often dysregulated during cancer development. In order to study tissue patterning, temporal and spatial resolution of communication between single cells is required. To explore how this complex process is controlled, we developed a patient-derived organoid screening platform to study both tissue patterning and kinase pathway dynamics in single cells across hundreds of conditions. Unlike normal and polyp-derived organoids, tumor organoids displayed a lack of patterning reminiscent of in vivo dysplasia. Using this system, we discovered that waves of Erk signaling induced by apoptotic cells are critical for maintaining tissue patterning in human colonic organoids. Using a small molecule-based screen, we discovered novel kinases which limit Erk activation across tissues and help maintain patterning. Perturbation of Erk restricting kinases results in dysfunctional colonic wound repair and re-establishment of tissue patterns in vivo. Citation Format: Kelvin W. Pond, Jayati Chakrabarti, Curtis A. Thorne, Andrew L. Paek. ERK dynamics are essential for colon tissue patterning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 171.
The usefulness of metabolic score for insulin resistance for the prediction of incident non-alcoholic fatty liver disease in Korean adults
Authors: Jun-Hyuk Lee, Kyongmin Park, Hye Sun Lee, Hoon-Ki Park, Jee Hye Han, Sang Bong Ahn
Journal: Clinical and Molecular Hepatology (2022)

The early detection and prevention of non-alcoholic fatty liver disease (NAFLD) has been emphasized considering the burden of this disease. Both hepatic and peripheral insulin resistances are strongly associated with NAFLD. We aimed to compare the predictive powers of a hepatic insulin resistance index, the homeostatic model assessment for insulin resistance (HOMA-IR), and a novel peripheral insulin resistance index, the metabolic score for insulin resistance (METS-IR), for the prediction of prevalent and incident NAFLD. Data from 8,360 adults aged 40-69 years at baseline and 5,438 adults without NAFLD who were followed-up at least once after the baseline survey in the Korean Genome and Epidemiology Study were analyzed. The survey was performed biennially, up to the eighth follow-up. The predictive powers of the METS-IR and HOMA-IR for prevalent NAFLD were not significantly different (area under the receiver operating characteristic [ROC] curve [95% confidence interval]: METS-IR, 0.824 [0.814-0.834]; HOMAIR, 0.831 [0.821-0.842]; P=0.276). The area under the time-dependent ROC curve (Heagerty's integrated area under the curve) of the METS-IR for incident NAFLD was 0.683 (0.671-0.695), significantly higher than that of the HOMA-IR (0.551 [0.539-0.563], P<0.001). The METS-IR is superior to the HOMA-IR for the prediction of incident NAFLD and is not inferior to the HOMA-IR for the prediction of prevalent NAFLD. This suggests that the METS-IR can be a more useful insulin resistance index than the HOMA-IR for the early detection and prevention of NAFLD in Korean population.
Abstract 4149: Knock-down of Neuropilin-1 by locked nucleic acid antisense oligonucleotides facilitates cancer immune control
Authors: Andre Maaske, Nicole Kirchhammer, Julia Festag, Laura Fernandez Rodriguez, Mélanie Buchi, Monika Schell, Stefanie Raith, Sven Michel, Richard Klar, Alfred Zippelius, Frank Jaschinski
Journal: Cancer Research (2022)

Abstract Immune checkpoint inhibitors have become an important tool for the treatment of cancer. However, the majority of patients does not respond to the currently employed antibody-based treatments, indicating a need for additional targets and new treatment modalities. The invention of 3rd generation chemistries like locked nucleic acids (LNAs) has allowed the development of highly specific and efficacious antisense oligonucleotides (ASOs) that allow target knockdown in vivo without the need for complex delivery formulations. The membrane-bound protein neuropilin-1 (NRP1) was initially identified as a factor involved in cell migration, -survival, and neoangiogenesis making it an attractive target for cancer therapy. It was subsequently shown that it has additional immune-mediated pro-tumorigenic roles. It can suppress anti-tumor immune activity via regulation of trafficking of tumor-associated macrophages, phenotypic stability of Tregs, and exhaustion of effector T cells. Considering that these effects are mediated by multiple domains of NRP1, there is a conceptual advantage to down-regulate the expression of the whole protein over the functional or steric blockade of individual domains. We used our in-house Oligofyer™ bioinformatics system to design both human NRP1 specific LNAplus™ ASOs, as well as murine surrogates, which both achieved target knock-down of more than 85% in vitro. Furthermore, the murine surrogate down regulated NRP1 in tumor mouse models. Systemic application of mouse-specific ASOs without additional carriers or adjuvants has led to a strong delay of tumor growth or complete eradication in syngeneic mouse models. This effect was almost completely abrogated in immune-compromised NSG mice. Furthermore, re-challenge of immune-competent mice after tumor eradication did not result in new tumor growth, suggesting induction of a long-lasting immunity by LNAplus™ ASO-mediated knockdown of NRP1. Taken together, these encouraging results indicate that the ASO-mediated down-regulation of NRP1 has the potential to become a promising treatment option for patients in need. We are currently performing further experiments to fully elucidate the mechanisms that underlie the observed anti-tumor efficacy. Citation Format: Andre Maaske, Nicole Kirchhammer, Julia Festag, Laura Fernandez Rodriguez, Mélanie Buchi, Monika Schell, Stefanie Raith, Sven Michel, Richard Klar, Alfred Zippelius, Frank Jaschinski. Knock-down of Neuropilin-1 by locked nucleic acid antisense oligonucleotides facilitates cancer immune control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4149.
Abstract 295: Superior efficacy of targeted nanoparticle therapy for brain tumors
Authors: HyungGyoo Kang, Jon Nagy, Bryon Upton, Timothy Triche
Journal: Cancer Research (2022)

Abstract Glioblastoma Multiforme is an incurable malignant brain tumor. Despite intensive efforts over many years, the prognosis is essentially unchanged. The primary reason is failure of otherwise effective therapy to reach the tumor, due to the blood brain barrier (BBB). To circumvent this functional barrier, we have developed CD99 and CD276 targeted irinotecan (Ir) containing liposomal nanoparticles (TNS: Targeted NanoSpheres) TNSs effectively penetrate the BBB and selectively bind to GBM cells while largely bypassing normal brain tissue. CD99 or CD276 targeted Ir-TNSs prolonged survival five-fold over free Ir treated animals in bi-weekly single dose level studies. Normal tissue levels were negligible, and no treatment-related toxicity was observed. QD dose intensification induced tumor regression in animals with progressive tumor. Anti-tumor effect was equivalent for either CD99 or CD276 Ir-TNSs. These results imply that intracranial therapy with otherwise effective drugs that do not pass the BBB is both feasible and shows superior efficacy over free drug therapy. Further, widespread expression of CD276 by many malignancies implies this therapy could be effective for metastatic brain tumors and extra-cranial malignancies as well. Citation Format: HyungGyoo Kang, Jon Nagy, Bryon Upton, Timothy Triche. Superior efficacy of targeted nanoparticle therapy for brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 295.
mRNA vaccine boosting enhances antibody responses against SARS-CoV-2 Omicron variant in individuals with antibody deficiency syndromes
Authors: Ofer Zimmerman, Alexa Michelle Altman Doss, Paulina Kaplonek, Chieh-Yu Liang, Laura A. VanBlargan, Rita E. Chen, Jennifer Marie Monroy, H. James Wedner, Anthony Kulczycki, Tarisa L. Mantia, Caitlin C. O’Shaughnessy, Hannah G. Davis-Adams, Harry L. Bertera, Lucas J. Adams, Saravanan Raju, Fang R. Zhao, Christopher J. Rigell, Tiffany Biason Dy, Andrew L. Kau, Zhen Ren, Jackson S. Turner, Jane A. O’Halloran, Rachel M. Presti, Daved H. Fremont, Peggy L. Kendall, Ali H. Ellebedy, Galit Alter, Michael S. Diamond
Journal: Cell Reports Medicine (2022)

Individuals with primary antibody deficiency (PAD) syndromes have poor humoral immune responses requiring immunoglobulin replacement therapy. We followed individuals with PAD after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination by evaluating their immunoglobulin replacement products and serum for anti-spike binding, Fcγ receptor (FcγR) binding, and neutralizing activities. The immunoglobulin replacement products tested have low anti-spike and receptor-binding domain (RBD) titers and neutralizing activity. In coronavirus disease 2019 (COVID-19)-naive individuals with PAD, anti-spike and RBD titers increase after mRNA vaccination but wane by 90 days. Those vaccinated after SARS-CoV-2 infection develop higher and more sustained responses comparable with healthy donors. Most vaccinated individuals with PAD have serum-neutralizing antibody titers above an estimated correlate of protection against ancestral SARS-CoV-2 and Delta virus but not against Omicron virus, although this is improved by boosting. Thus, some immunoglobulin replacement products likely have limited protective activity, and immunization and boosting of individuals with PAD with mRNA vaccines should confer at least short-term immunity against SARS-CoV-2 variants, including Omicron.